Is SETD1B p.Thr482Met (c.1445C>T) pathogenic?

SETD1B p.Thr482Met (c.1445C>T) is classified Uncertain significance in SETD1B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-10). AlphaMissense: ambiguous (0.5534); Very rare (popmax 0.0014%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SETD1B p.Thr482Met (c.1445C>T)?

SETD1B p.Thr482Met (c.1445C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SETD1B p.Thr482Met (c.1445C>T) in the general population?

SETD1B p.Thr482Met (c.1445C>T) is very rare (popmax 0.0014%, nfe) (gnomAD).

What do computational predictors say about SETD1B p.Thr482Met (c.1445C>T)?

AlphaMissense predicts ambiguous (score 0.5534) — an in-silico prediction, not a clinical call.

SETD1B p.Thr482Met

c.1445C>T · VCV3440168

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5534 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0014%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5534	ambiguous
REVEL	0.42	indeterminate
SaProt	LLR -8.98	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 795 bp · p 0.65 · regional, not allelic
Overall
CADD	26.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0014% European (non-Finnish) · 16/1,146,922 alleles

Filtering AF 0.000826% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.00123% 19/1,548,534 alleles · very rare exomes 17/1,396,322 · genomes 2/152,212 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00167%	60,060
European (non-Finnish)grpmax	0.0014%	71,683
African / African-American	0.00137%	73,044
South Asian	0.00119%	84,060

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: SETD1B
Protein: p.Thr482Met
Coding: c.1445C>T
MANE Select: NM_001353345
Type: single nucleotide variant
Location: chr12:121810390 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 46.43 · 4 PDB
Residue 482: the 'disordered' region

Full SETD1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SETD1B p.Ala1657Val Uncertain significance ★★ ⚠ same condition
SETD1B p.Ala654Thr Uncertain significance ★★ ⚠ same condition
SETD1B p.Arg1428Trp Uncertain significance ★★ ⚠ same condition
SETD1B p.Arg1458His Uncertain significance ★★ ⚠ same condition
SETD1B p.Arg1643His Uncertain significance ★★ ⚠ same condition
SETD1B p.Arg1670Gln Uncertain significance ★★ ⚠ same condition
SETD1B p.Arg467Gln Uncertain significance ★★ ⚠ same condition
SETD1B p.Asp1107Asn Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/setd1b-p-thr482met (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown